The mucosa (or mucous membranes) lines various body cavities that are exposed to the external environment. It is at several places continuous with skin: at the nostrils, the lips, the ears, the genital area, and the anus. The mucosa is composed of nonkeratinised stratified squamous epithelium. Its function is to serve as a barrier to protect the underlying tissues and organs.
Inflammation is a complex biological response of vascular tissues and immune cells to harmful stimuli, such as pathogens, damaged cells, or irritants, like for instance chemotherapeutic agents or radiotherapy. It is characterized by five signs: rubor (redness), calor (increased heat), tumor (swelling), dolor (pain), and/or functio laesa (loss of function). Many kind of inflammatory disorders of the mucosa can appear. Some non limiting examples of inflammatory disorders are: mucositis, stomatitis, lichen planus, periodontal disease, aphtous ulcers, oesophagitis, rectitis, rectocolitis, and Crohn's disease. Inflammation is often cause of pain, like orodental and orofacial pain.
The function of mucosa, as described above, is particularly important for the oral mucosa (the mucous membrane of the inside of the mouth), the pharynx mucosa and the larynx mucosa. Indeed, the oral cavity, the pharynx and the larynx are an entrance to the digestive tract or the respiratory organ and are susceptible to many stimulations and injuries and cause many kinds of inflammation such as mucositis, stomatitis, lichen planus, periodontal disease, aphtous ulcers, orodental and orofacial pain. These painful inflammation diseases occur, in particular in the case of anticancer therapies.
One frequent complication of radiotherapy and chemotherapy is the damage called mucositis that occurs in the mucosa, and more particularly in the mucosal lining of the mouth, the pharynx and/or the larynx.
Oral ulcerative mucositis is a common, painful, dose-limiting toxicity of drug and radiation therapy for cancer (Scully C, Sonis S, Diz P D. Oral mucositis. Oral Dis 2006;12:229-41). The disorder is characterized by breakdown of the oral mucosa that results in the formation of ulcerative lesions. In granulocytopenic patients, the ulcerations that accompany mucositis are frequent portals of entry for indigenous oral bacteria often leading to sepsis or bacteremia (Donnelly J P, Bellm L A, Epstein J B, Sonis S T, Symonds R P. Antimicrobial therapy to prevent or treat oral mucositis. Lancet Infect Dis 2003;3:405-12).
Mucositis occurs to some degree in more than one third of patients receiving anti-neoplastic drug therapy (Sonis S T, Elting L S, Keefe D, et al. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 2004;100:1995-2025). The frequency and severity are significantly greater among patients who are treated with induction therapy for leukemia or with many of the conditioning regimens for bone marrow transplant (Vera-Llonch M, Oster G, Ford C M, Lu J, Sonis S. Oral mucositis and outcomes of allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies. Support Care Cancer 2007;15:491-6). Among these individuals, moderate to severe mucositis is not unusual in more than three-quarters of patients. Moderate to severe mucositis occurs in virtually all patients who receive chemotherapy and/or radiation therapy for tumors of the head and neck.
Clinically mucositis progresses through three stages:                1. Early, painful mucosal erythema, which can be palliated with local anesthetics or non-narcotic analgesics.        2. Painful ulceration with pseudomembrane formation and, in the case of myelosuppressive treatment, potentially life-threatening sepsis, requiring antimicrobial therapy. Pain is often of such intensity as to require parenteral narcotic analgesia.        3. Spontaneous healing, occurring about 2-3 weeks after cessation of anti-neoplastic therapy.        
The complexity of mucositis as a biological process has only been recently appreciated (Sonis S T. Pathobiology of oral mucositis: novel insights and opportunities. J Support Oncol 2007;5:3-11), indicating that the fundamental mechanisms involved in the pathogenesis of mucositis are much more complex than direct damage to epithelium alone. Mechanisms for radiation-induced and chemotherapy-induced seem to be similar. It has been suggested that the condition represents a sequential interaction of oral mucosal cells and tissues, reactive oxygen species, pro-inflammatory cytokines, mediators of apoptosis and local factors such as saliva and the oral micro biota. While epithelial degeneration and breakdown ultimately result in mucosal ulceration, it appears that the early changes associated with radiation-induced mucosal toxicity occur within the endothelium, and connective tissue of the submucosa.
Standard therapy for mucositis is predominantly palliative and focused on pain control and maintenance of nutrition. However, recent data indicates that even opiods are often insufficient to control mucositis pain. Currently, the only approved treatment for mucositis is palifermin (Kepivance®), and its application is limited to mucositis in patients undergoing conditioning regimens prior to hematopoietic stem cell transplant.
In addition to the symptoms of mucositis and its impact on quality of life, mucositis adversely affects a variety of other health and economic outcomes. The duration of hospitalization and risks of serious infection are significantly increased in patients with oral mucositis, which results in an increase of use of resources and higher costs. Mucositis also threatens the efficacy of treatment plans by necessitating breaks in radiation therapy, reductions in doses of drugs used in chemotherapy and modifications in the selection of antineoplastic agents. There are currently many different treatments that are known to prevent or treat inflammatory pain and diseases in mucosa in the oral cavity, pharynx and larynx These treatments can be generally categorized as general oral care protocols, interventions to reduce the mucosal toxicity of chemotherapy drugs, mouthwashes with mixed actions, immunomodulatory agents, topical anesthetics, antibacterial, antifungal and antiviral agents, cytoprotectants, mucosal cell stimulants, psychotherapy and analgesics.
As the general oral care protocol regimens including dental work to eliminate caries and existing gum disease, as well as the frequent cleaning of the oral cavity can be undertaken.
Cryotherapy or allupurinol mouthwash can be used to minimize or prevent mucositis, as well as mouthwashes with mixed actions such as those containing benzydamine hydrochloride, corticosteroids and/or chamomile. Mucosal barriers such as sucralfate which binds electrostatically to ulcers, including gastric and oral ulcers is also being used in patients at risk of getting mucositis.
Cytoprotectants such as beta-carotene, vitamin E and oxpentifylline have also been tried to ameliorate mucositis in cancer patients. Low energy laser treatments, silver nitrate and glutamine have also been tried to decrease the duration of mucositis. Analgesics such as opioids are also generally used to reduce pain. Immunomodulatory agents such as granulocyte-macrophage colony stimulating factor (GM-CSF), keratinocyte growth factor-1 and granulocyte stimulating factor (G-CSF) have been administered and can be effective in reducing and preventing the duration of mucositis. Topical anesthetics, antiseptics, antibacterial, antifungal and antiviral agents have also been used to treat or prevent mucositis.
These different treatments are still insufficient for preventing and treating inflammatory pain and diseases in mucosa. It is therefore extremely important that inflammatory pain and diseases in mucosa, particularly in mucosa of the oral cavity, the pharynx and the larynx, be prevented or treated to reduce the severe conditions of the patients. Among inflammatory pain and diseases, the mucositis, and particularly mucositis of the oral cavity, the pharynx and the larynx, needs the development of new treatments.
Alpha-2 adrenergic receptor agonists play a key role in smooth muscle contraction and neurotransmitter inhibition. Alpha-2-adrenergic agonists crossing the blood-brain barrier have a hypotensive effect and are called sympatholytic and centrally acting hypotensive drugs.
Clonidine hydrochloride, also known as catapressan® is a centrally acting alpha-2 adrenergic agonist that stimulates the alpha-2 adrenoreceptors in the brain stem. It is generally used as an anti-hypertensive agent. However recently new uses for clonidine are under consideration for a variety of ailments. For example, clonidine can be used to treat insomnia or menopausal symptoms. It can also be used to treat some types of neuropathic pain (Joel B. Epstein and al, Journal of Orofacial pain 1997, volume 11, number 4 pp 346-352). However, the causative mechanisms of neuropathic pain are different compare to those of inflammation pain. Indeed neuropathic pain is produced by damage to, or pathological changes in the peripheral or central nervous systems. Examples of pathological changes include prolonged peripheral or central neuronal sensitization, central sensitization related damage to nervous system inhibitory functions, and abnormal interactions between the somatic and sympathetic nervous systems. The hallmarks of neuropathic pain are chronic allodynia and hyperalgesia. Examples of neuropathic pain include: monoradiculopathies, trigeminal neuralgia, postherpetic neuralgia, phantom limb pain, complex regional pain syndromes and the various peripheral neuropathies. Neuropathic pain tends to be only partially responsive to opioid therapy. In other applications clonidine is used to treat attention-deficiency hyperactivity disorder, as well as Tourette syndrome. However clonidine has never been used to treat inflammatory pain and diseases in mucosa, particularly mucosa of the oral cavity, pharynx or larynx and more particularly oral mucositis.
There are many different systems known in the art to deliver alpha-2 adrenergic receptor agonists, besides the regular pill formulations. For instance, U.S. Pat. No. 4,201,211 describes a therapeutic system in the form of a skin patch that administers clonidine transdermally in an initial priming dose of 10 to 300 μg/cm2 of skin that brings the concentration of clonidine in the blood to a level sufficient to elicit alpha-adrenergic stimulation without intolerable side effects, followed by a substantially constant continuous dosage in the range of 0.1 to 100 μg/hr that maintains this level. The system is a four-layer laminate of, from the top: a protective backing; a gelled, mineral oil-polyisobutene-clonidine reservoir lamina that is the source of the clonidine for the continuous constant dosage; a microporous membrane that controls the constant dosage rate; and a gelled, mineral oil-polyisobutene-clonidine contact adhesive layer that is the source of the clonidine for the priming dose and the means by which the system is attached to the skin. This patent describes the use of clonidine to treat hypertension.
U.S. Pat. No. 5,175,052 describes an adhesive tape preparation of clonidine comprising a polytetrafluoroethylene porous sheet having an air permeability of from 10 to 500 seconds having thereon an active ingredient-containing layer comprising a pressure-sensitive adhesive obtained by copolymerizing a monomer mixture comprising from 40 to 80% by weight of 2-ethylhexyl acrylate, from 20 to 60% by weight of 2-methoxyethyl acrylate, and 0 to 40% by weight of vinyl acetate, the pressure-sensitive adhesive containing clonidine to treat hypertension as an active ingredient. The preparation achieves sustained release of clonidine and exhibits long-term preservability while minimizing skin irritation and maintaining sufficient adhesion to the skin.
A clonidine preparation for percutaneous administration comprising a support having provided thereon an active ingredient-containing layer is disclosed in U.S. Pat. No. 4,765,974. The active ingredient-containing layer contains an acrylic polymer having a glass transition temperature of from −70° C. to −10° C. and pressure-sensitive adhesion at room temperature as a base, at least one of clonidine and clonidine hydrochloride as an active ingredient, and a decomposition inhibitor. The active ingredient can be stably maintained within the preparation without being decomposed, and, therefore, can be effectively released over a prolonged period of time.
There is disclosed a polymeric diffusion matrix for the sustained release of clonidine to treat hypertension by transdermal delivery to a patient wherein the matrix comprises a polar plasticizer, polyvinylalcohol, polyvinylpyrrolidone, and a pharmaceutically effective amount of clonidine in U.S. Pat. No. 4,292,303.
However, none of the above patents describe the mucosal delivery of at least one alpha-2 adrenergic receptor agonist or the use thereof to prevent or treat inflammatory pain and diseases in mucosa, and notably mucosa of the oral cavity, the pharynx and/or the larynx. Thus, there is a need in the art to prevent or treat inflammatory pain and diseases in mucosa, and notably mucosa of the oral cavity, the pharynx and/or the larynx in an effective manner and especially in cancer or immunodepressed patients or mammals such that cancer treatment can be maintained in successive treatments.
Therefore it is an object of the present invention to prevent or treat inflammatory pain and/or diseases in mucosa, and notably, but not only, mucosa of the oral cavity, the pharynx and/or the larynx, using at least one alpha-2 adrenergic receptor agonist and/or at least one pharmaceutically acceptable salt thereof.
In particular, it is an object of the present invention to prevent or treat mucositis using clonidine, clonidine hydrochloride, clonidine derivatives or mixtures thereof.
It is another object of the present invention to provide a mucosal bioadhesive slow release carrier for mucosal delivery of at least one alpha-2 adrenergic receptor agonist, and/or at least one pharmaceutically acceptable salt thereof.
It is yet another object of the present invention to provide a mucosal delivery bioadhesive slow release carrier in which the at least one alpha-2 adrenergic receptor agonist and/or at least one pharmaceutically acceptable salt thereof can be administered to prevent or treat inflammatory pain and diseases in mucosa and notably, but not only, mucosa of the oral cavity, the pharynx and/or the larynx.
It is yet another object of the present invention to provide a mucosal bioadhesive slow release carrier that can contain a bioadhesive agent of synthetic, vegetal or animal origin, preferably from milk proteins or of pea protein origin that contains at least one alpha-2 adrenergic receptor agonist, and/or at least one pharmaceutically acceptable salt thereof to prevent or treat inflammatory pain and/or diseases in mucosa and notably, but not only, mucosa of the oral cavity, the pharynx and/or the larynx.
Yet another object of the present invention is a method for delivering at least one alpha-2 adrenergic receptor agonist, and/or at least one pharmaceutically acceptable salt thereof to a mammal to prevent or treat inflammatory pain and/or diseases in mucosa and notably, but not only, mucosa of the oral cavity, the pharynx and/or the larynx.
Methods of preventing or treating inflammatory pain and/or diseases in mucosa and notably, but not only, mucosa of the oral cavity, the pharynx and/or the larynx are also objects of the present invention using at least one alpha-2 adrenergic receptor agonist and/or at least one pharmaceutically acceptable salt thereof.
Use of the mucosal bioadhesive slow release carrier for the manufacture of medicaments containing at least one alpha-2 adrenergic receptor agonist, and/or at least one pharmaceutically acceptable salt thereof to prevent or treat inflammatory pain and/or diseases in mucosa and notably, but not only, mucosa of the oral cavity, the pharynx and/or the larynx, is also an object of the present invention.
Yet another object is the use of at least one alpha-2 adrenergic receptor agonist, and/or at least one pharmaceutically acceptable salt thereof for preventing or treating inflammatory pain and/or diseases in mucosa and notably, but not only, mucosa of the oral cavity, the pharynx and/or the larynx.
These and other objects are achieved by the present invention as evidenced by the summary of the invention, description of the preferred embodiments and the claims.